The goal of this project is to define in detail the potential efficacy of therapeutic moderate hypothermia in victims of severe traumatic brain injury (TBI) and to determine the neurochemical and physiologic mechanisms of its action. We also will determine the prevalence of local and global cerebral ischemia following severe TBI, and the effects of traditional treatments for intracranial pressure on the incidence of local cerebral ischemia. During the last 2 years, we studied the clinical and physiologic effects of moderate hypothermia in a randomized prospective trial and found that is significantly reduces ICP, improves cerebral metabolism, and shows a trend toward improved neurologic outcome. We believe that these effects are partially due to a decrease in the local tissue concentrations of neurochemical mediators of cerebral ischemia. Our clinical studies also have shown that clinical outcome may be improved by management strategies aimed at alleviating cerebral ischemia by enhancing cerebral perfusion. This is consistent with our hypothesis that local cerebral ischemia is common after severe head injury. Although this hypothesis is not clearly supported by studies of regional cerebral blood flow (CBF) using noninvasive (xenon) techniques or SPECT, these techniques cannot resolve flow to small regions of the brain. Furthermore, CBF values otherwise considered in the ischemic range might be adequate after TBI if metabolism is also suppressed, as has been suggested. Because ischemia is in part defined by the metabolic needs of the tissue, the identification of ischemia requires measurement of cerebral metabolism as well as CBF. During the next 5 years, we will investigate neurochemical mechanical mechanisms responsible for the effects of therapeutic hypothermia and delineate the prevalence and potential causes of local cerebral ischemia using in-vivo microdialysis and local CBF-monitoring techniques. Patients with severe TBI (approximately 25/year) will be randomized in a prospective study of therapeutic moderate hypothermia. Those randomized to the experimental arm will be cooled to 32-33degreesC for 48 hours. With the use of in- vivo microdialysis and cortical CBF probes, we will sample the extracellular concentration of lactate, pyruvate, glutamate and malondialdehyde, a metabolite of free radicals. We will correlate the level of these intermediates of secondary brain injury with local CBF values. The probes will be placed adjacently in regions of the brain most likely to be ischemic-near contusions or posttraumatic hematomas-- after surgery to remove these lesions. We also will determine the effect of therapeutic hypothermia and of measures used to treat intracranial hypertension (hyperventilation, mannitol, CSF drainage) on the release of these neurochemicals. Finally, we will assess efficacy of therapeutic hyperthermia with MRI scans obtained 6 months after injury. Our findings are expected to guide the more appropriate use of conventional therapy for TBI and help to establish the efficacy of a new therapy (moderate hypothermia), thus leading to improved outcome.